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Natural and induced control of HIV infection:differences and similarities
VISCONTI Study
Asier Sáez-Cirión, PhDUnité de Régulation des Infections Rétrovirales
Institut Pasteur, Paris, France
At least 5 years of infection, naïve of cARV, maintain 5 last viral loads < 400 copies
Buffassa et al, PLoS One 2011
HIV controllers (HIC): infected individuals
spontaneously controlling HIV-1 infection
Year01 02 03 04 05 06 07 08 09 10
CD4+
T c
ells
/mm
30
500
1000
1500
2000
HIV
-1 R
NA
(cop
ies/
ml p
lasm
a)
100101102103104105106107108109
Post-treatment controllers (PTC): infected individualscontrolling HIV-1 infection after interruption of cART
14 patientsMonths on cART : 36.5 (12-92)Months post-cART: 89 (48-115)
Therapy started within 10 weeks following Primary Infection (median 39 days p.i.)
Saez-Cirion et al PLoS Path 2013
1990 1995 2000 2005 2010
CD4
T ce
ll co
unts
/µl
0
200
400
600
800
1000
HIV
-1 R
NA
(cop
ies/
ml p
lasm
a)0
500
1000
1500
2000
2500
HIV controllers and Post-treatment controllers different ways for a similar outcome
Post-treatment controllers had a tougher primary infection than HIV controllers
pre-HIC pre-PTC PRIMO Non controllers
CD4+
T c
ells
cou
nts
at P
HI
(cel
ls/µ
l)
200
400
600
800
1000
1200
pre-HIC pre-PTC PRIMO Non controllers
Plas
ma
RNA
Vira
l loa
d at
PH
I(lo
g co
pies
/ml)
0
2
4
6
8p=0.02
p=0.002p=0.88
p=0.68
Saez-Cirion et al PLoS Path 2013
Post-treatment controllers do not have a favorable MHC background
France HIC
Alle
le fr
eque
ncy
(%)
0
10
20
30
40
50
60
PTC
B27 B57 B35 B07
Saez-Cirion et al PLoS Path 2013
Saez-Cirion et al, JI 2009
R=0.836, p<0.00001
log p24 decrease (CD4 vs CD4:CD8 1:1)
0 1 2 3 4 5IF
Ng
SFC
tota
l/10
6 PBM
C0
2000
4000
6000
8000
10000
12000
14000
16000
Days post infection3 7 10
p24
(ng/
ml)
10-1
100
101
102
103
10 4
CD4 T cellsCD4:CD8 1:1
Saez-Cirion et al, PNAS 2007; Nature Protocols 2010
Efficient T cell responses are associated with natural control
• Greater and faster upregultaion of cytotoxic mediators Migueles, et al. Immunity 2008; Hersperger, et al. PLoS Pathogens 2010
% I
L-2
+C
D4+
T c
ells
0.001
0.01
0.1
1
PHI HIC0.001
0.01
0.1
1
PHI HIC
% IF
Ng
+ CD
4+ T c
ells
0.001
0.01
0.1
1
10
PHI HIC0.001
0.01
0.1
1
10
PHI HIC
P=0.048
% I
L-2
+C
D8+
T c
ells
% IF
Ng
+ CD
8+ T c
ells
Lecuroux et al PLoS One, 2013
HICPHIlog
p24
dec
reas
e (
CD
4 vs
CD
4:C
D8
1:1)
0
1
2
3
4
5
P < 0.001
Strong CD8- T cell capacity to suppress HIV-1 is usually absent in PHI
Median drop of -0.94 log HIV-1 RNA copies/ml within 7 days50 patients in PHI (median 35 days p.i.)
Post-treatment controllers have weak HIV-specific CD8+ T cell responses
VIR HAART HIClo
g p2
4 de
crea
se (C
D4
vs C
D4:
CD8)
0
1
2
3
4
<0.001
<0.001
VIR HAART HIC
IFNg
(SFC
/106 P
BMC)
0
2000
4000
6000
8000
10000
12000
IFNg ELISPOT
<0.001
<0.001
<0.01<0.01
PTC
<0.001
PTC
Saez-Cirion et al PLoS Path 2013
HIV suppression
Post-treatment controllers have weak levels of T cell activation
CD38+ HLA-DR+ CD38+HLA-DR+
% o
f CD
3+ C
D8+
cel
ls
0
10
20
30
40
50
60
70
HAARTHICPTC
p < 0.001
p < 0.001
Saez-Cirion et al PLoS Path 2013
Both HIC and PTC are infected with replication competent HIV-1
days of culture
0 5 10 15 20 25 30p24
in c
ulu
re s
up
ern
atan
ts p
24 (
ng
/ml)
0.01
0.1
1
10
100
1000
Viral replication in CD4+ T cells from healthy donor
3538 patients included in the FHDH within 6 months of primary infection 1997-2011
756 patients treated within 6 months and at least for a year
74 patients with a viral load below <50 RNA copies/ml who stop = 2% of PHI patients
Goujard et al Antivir Ther 2012: N=164 patients, 8.5% VL<50 at M24
Hocqueloux et al AIDS 2010: N=32 patients, 15.6% VL<50 at M24
Probability to keep controlling infection at 24M (loss of control: 2VL>50 RNA copies/ml or 1VL>50 RNA copies/ml +cART) : 15.7% [6.5-28.5]
Months post-treatment interruption
Prob
abili
ty to
loss
con
trol
Saez-Cirion et al PLoS Path 2013
A long-term treatment initiated during primary infection seems to increase the chances to control viremia
HIC vs PTC
HIV controllers (HIC)
Asymptomatic primary infection: low viral loads and high CD4 T cell counts in PHI
80% HIC carry one protective HLA-class I allele
Generally strong HIV-specific T cell responses with strong capacity to eliminate infected cells
Abnormal high levels of T cell activation
Estimated frequency: 0.5% of HIV infected patients
Post-Treatment Controllers (PTC)
Symptomatic primary infection: high viral loads and low CD4 T cell counts in PHI
57% PTC carry one HLA-class I allele associated with high viral loads
Generally very weak HIV-specific T cell responses with poor capacity to eliminate infected cells
Low levels of T cell activation
Estimated frequency: 5-15% of HIV infected patients interrupting a >12 months-length treatment initiated in primary infection
Exploring other mechanisms that have been proposed to contribute to natural control of infection…
Weak cell susceptibility to HIV-1 infection, contributing to limit the reservoirs in HIC
Innate immunity, NK cells, may contribute to limit replication in acute infection
Enhanced ADCC activity may contribute to control of infection, in particular in HLA-B*57neg HIC
Acknowledgements
Institut PasteurRégulation des Infections Rétrovirales
Gianfranco PancinoDaniel Scott-Algara
Françoise Barré-SinoussiAnnie David
Pierre Versmisse Faculté de Médecine Paris SudINSERM U1012
Alain VenetOlivier Lambotte
Jean-François DelfraissyCécile GoujardIsabelle Girault
Camille Lecuroux
INSERM U1018Laurence Meyer
Faroudy Boufassa
CHU Necker Enfants MaladesLaboratoire de Virologie
Christine RouziouxVéronique Avettand-Fenoel
Adeline Mélard
CHR Orléans La SourceService Maladies Infectieuses
Laurent HocquelouxThierry Prazuck
CHU Hôtel-DieuUnité Immuno-Infectiologie
Jean-Paul Viard
ANRS CO18 “HIV controllers”
ANRS CO15 “ALT”
Patients and clinicians who participate in the studyCHU Pitié-SalpetriereINSERM UMR-S 945
Brigitte AutranCharline Bacchus
Benjamin DescoursAssia Samri
Ioannis TheodorouJulien Guergnon
ANRS CO6 “PRIMO”
INSERM UPMC U943Dominique Costagliola
Valérie Portard
FHDH“French Hospital Database on HIV”